Systems and Methods for Compensating Long Term Sensitivity Drift of Electrochemical Gas Sensors Exposed to Nitric Oxide

ABSTRACT

Described are systems and methods for compensating long term sensitivity drift of catalytic type electrochemical gas sensors used in systems for delivering therapeutic nitric oxide (NO) gas to a patient by compensating for drift that may be specific to the sensors atypical use in systems for delivering therapeutic nitric oxide gas to a patient. In at least some instances, the long term sensitivity drift of catalytic type electrochemical gas sensors can be addressed using calibration schedules, which can factor in the absolute change in set dose of NO being delivered to the patient that can drive one or more baseline calibrations. The calibration schedules can be used reduce the amount of times the sensor goes offline. Systems and methods described may factor in in actions occurring at the delivery system and/or aspects of the surrounding environment, prior to performing a baseline calibration, and may postpone the calibration and/or rejected using the sensor&#39;s output for the calibration.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit under 35 U.S.C. §119(e) to U.S.Provisional Application No. 61/941,725, filed Feb. 19, 2014, the entirecontents of which are incorporated herein by reference in theirentirety.

FIELD

The present invention generally relates to systems and methods forcompensating long term sensitivity drift of electrochemical gas sensorsexposed to nitric oxide, for example, in a controlled environment.

BACKGROUND

There exist many variations of electrochemical sensors which, althoughthey may appear similar, function vastly differently. For example, someelectrochemical sensors can be used for detection of the presence of aspecific gas while others detect concentrations of a specific gas. Evenfurther some electrochemical sensors function with liquids and do notfunction with gases. Focusing on electrochemical gas sensors, some ofthese gas sensors use galvanic reactions while others use catalyticreactions. Further, some of these gas sensors need electricity tofunction while others do not need electricity and in some instancesthese sensors actually generate electricity. Even further, withinsimilar types of electrochemical gas sensors that have the sameelectrical requirements, this small subset of sensors can have a vastamount of variation depending on the function of the cell and/or the gaswhich the cell reacts with.

Focusing on catalytic type electrochemical gas sensors, these sensorsare typically used as toxic gas sensors. When used as toxic gas sensors(e.g., for monitoring of smoke stacks emissions) these sensors may onlybe exposed to the toxic gas for short durations of time or intermittentduty times and/or they may only be used to detect significantly lowconcentrations of a gas (e.g., gas in the parts per billion (PPB)range). However, unlike the way these sensors are used as toxic gassensors, systems for delivering therapeutic nitric oxide gas to apatient can use catalytic type electrochemical gas sensors to confirmaccurate dosing of therapeutic gas such as inhaled nitric oxide (NO).These delivery systems, that include catalytic type electrochemical gassensors, can be used to deliver therapeutic nitric oxide to a patient ata dosage in the parts per million (e.g., 1 PPM to 80 PPM, 0.1 PPM to 80PPM, etc.) for a prolonged period of time (e.g., many hours, days,weeks, months, etc.) under continuous gas monitoring.

Generally speaking, this type of use of catalytic type electrochemicalgas sensors in systems for delivering therapeutic nitric oxide gas to apatient is considered to be atypical and may present problems not seenwhen using these sensors in a more conventional manner (e.g., typicaltoxic gas sensor applications). These issues, can be important as users(e.g., doctors, nurses, etc.) may confirm dosing of the therapeutic drugbased on the output of these sensors. Accordingly, a need exists toovercome these issues for at least ensuring proper confirmation ofdosing.

SUMMARY

There are several ways to address the above problems, including forexample performing recalibrations of the sensor over particular timeintervals, providing messages and/or indicators that warn a user ofoperating conditions and performance of calibrations, use of dualsensors to measure the amount of the target gas in a breathing circuit,and detecting if sensor output is beyond a threshold range.

Principles and embodiments relate generally to a method for compensatingfor output drift of an electrochemical gas sensor exposed to nitricoxide in a controlled environment, comprising identifying a time forexecuting a calibration from a sensor recalibration schedule stored in asystem controller memory, and detecting if an alarm is active or hasbeen active within a predetermined timeframe at the time the calibrationis to be executed, wherein the calibration is postponed if the activealarm is detected or has been detected within the predeterminedtimeframe, and execute the calibration if the active alarm is notdetected or has not been detected within the predetermined timeframe.

Embodiments also relate to establishing a dosage of a target gas to bedelivered to a breathing circuit indicated by a setting in a systemcontroller, identifying a change in the setting in the systemcontroller, calculating the magnitude of a change in the dosage of thetarget gas to be delivered to the breathing circuit, identifying thesensor recalibration schedule stored in the system controller memorythat is specified for the magnitude of the change in the dosage of thetarget gas, and implementing the sensor recalibration scheduleidentified.

Embodiments also relate to continuously measuring a concentration of thetarget gas in the breathing circuit with a first sensor, communicating asignal representative of the target gas concentration from the firstsensor to the system controller over a communication path, anddetermining a response by the first sensor to the change inconcentration of the target gas.

Embodiments also relate to interrupting the continuous measuring of thetarget gas concentration when indicated by the identified sensorrecalibration schedule, exposing the first sensor to a gas having a zeroconcentration of the target gas for a period of time sufficient todetect the output value indicative of the zero concentration, anddetermining the response by the first sensor to the gas having a zeroconcentration of the target gas.

Embodiments also relate to a sensor recalibration schedule comprises aset of values representing intended intervals between interruptions ofthe continuous measuring of the target gas concentration.

Embodiments also relate to an intended intervals are larger for asmaller change in the setting in the system controller.

Embodiments also relate to storing the response of the first sensor tothe gas having a zero concentration of the target gas in the systemcontroller memory.

Embodiments also relate to accessing a slope of a previous calibrationline stored in the system controller memory, and generating a newcalibration line using the stored response of the first sensor to thegas having the zero concentration of the target gas and the slope of theprevious calibration line.

Embodiments also relate to identifying the type of first sensorcontinuously measuring a concentration of the target gas in thebreathing circuit, storing the type of first sensor in the systemcontroller, and utilizing the type of first sensor in identifying thesensor recalibration schedule.

Embodiments also relate to a first sensor that is a three terminalelectrochemical nitric oxide gas sensor or a four terminalelectrochemical nitric oxide gas sensor.

Embodiments also relate to selecting a source of ambient air to flow tothe first sensor when interrupting the continuous measuring of thetarget gas concentration in the breathing circuit without disconnectinga sample line from an inspiratory side of the patient breathing circuit.

Embodiments also relate to switching a valve connected to and in fluidcommunication with the patient breathing circuit to allow ambient air toflow to the first sensor when interrupting the continuous measuring ofthe target gas concentration in the breathing circuit withoutdisconnecting a sample line from an inspiratory side of the patientbreathing circuit.

Embodiments also relate to verifying the valve has switched to allowambient air to flow to the sensor.

Embodiments also relate to postponing execution of the calibration by apredetermined time period, and detecting if an alarm is active or hasbeen active within a predetermined timeframe after the predeterminedtime period has elapsed, wherein the calibration is postponed if theactive alarm is detected or has been detected within a predeterminedtimeframe, and executed the calibration if the active alarm is notdetected or has been detected within a predetermined timeframe.

Embodiments also relate to (i) detecting the presence of interferinggas, and postponing execution of the calibration by a predetermined timeperiod if interfering gas is detected and/or (ii) detecting if a user isinteracting or has interacted with the therapeutic gas delivery systemwithin a predetermined timeframe at the time the calibration is to beexecuted.

Embodiments also relate to displaying a message to a user when measuringthe concentration of the target gas in the breathing circuit with thefirst sensor is interrupted to execute the calibration.

Embodiments also relate to measuring the concentration of the target gasin the breathing circuit with a second sensor when measuring theconcentration of the target gas in the breathing circuit with the firstsensor is interrupted, so a measure of the target gas concentration isdisplayed to a user during recalibration.

Embodiments also relate to exposing the second sensor to the gas havinga zero concentration of the target gas for the period of time sufficientto de-saturate and/or detect the output value indicative of the zeroconcentration after exposing the first sensor to the gas having a zeroconcentration of the target gas for the period of time sufficient tode-saturate and/or detect the output value indicative of the zeroconcentration, and comparing the output value from the second sensor tothe output value of the first sensor to determine the difference indrift between the first and second sensor.

Principles and embodiments also relate generally to a method forcompensating for output drift of an electrochemical gas sensor exposedto nitric oxide in a controlled environment, comprising identifying atime for executing a calibration from a sensor recalibration schedulestored in a system controller memory, detecting if an alarm is active orhas been active within a predetermined timeframe at the time thecalibration is to be executed, wherein the calibration is postponed ifthe active alarm is detected or has been detected within thepredetermined timeframe, detecting if a user is interacting or hasinteracted with the therapeutic gas delivery system within apredetermined timeframe at the time the calibration is to be executed,wherein the calibration is postponed if the user is interacting or hasinteracted with the therapeutic gas delivery system within thepredetermined timeframe, detecting if one or more interfering gasses arecausing or have caused sensor output to be outside a threshold rangewithin a predetermined timeframe at the time the calibration is to beexecuted, wherein the calibration is postponed if the sensor output isor has been out of range within the predetermined timeframe at the timethe calibration is to be executed, executing the calibration (i) if theactive alarm is not detected or has not been detected within thepredetermined timeframe, (ii) if the user is not interacting or has notinteracted with the therapeutic gas delivery system within thepredetermined timeframe, and (iii) if the sensor output is not or hasnot out of range within a predetermined timeframe.

Principles and embodiments also relate generally to a method forcompensating for output drift of an electrochemical gas sensor exposedto nitric oxide in a controlled environment, comprising delivering atherapeutic gas comprising NO to a patient in need thereof, detecting achange in set dose of the therapeutic gas, selecting a sensorrecalibration schedule stored in a system controller memory in responseto the change in set dose, identifying a time for executing acalibration from the selected sensor recalibration schedule, detectingif an alarm is active or has been active within a predeterminedtimeframe at the time the calibration is to be executed, wherein thecalibration is postponed if the active alarm is detected or has beendetected within the predetermined timeframe, detecting if a user isinteracting or has interacted with the therapeutic gas delivery systemwithin a predetermined timeframe at the time the calibration is to beexecuted, wherein the calibration is postponed if the user isinteracting or has interacted with the therapeutic gas delivery systemwithin the predetermined timeframe, detecting if one or more interferinggasses are causing or have caused sensor output to be outside athreshold range within a predetermined timeframe at the time thecalibration is to be executed, wherein the calibration is postponed ifthe sensor output is or has been out of range within the predeterminedtimeframe at the time the calibration is to be executed, executing thecalibration (i) if the active alarm is not detected or has not beendetected within the predetermined timeframe, (ii) if the user is notinteracting or has not interacted with the therapeutic gas deliverysystem within the predetermined timeframe, and (iii) if the sensoroutput is not or has not out of range within a predetermined timeframe,and displaying a message to a user, when executing a calibration,indicating that a calibration is in effect and/or recording in anelectronic medical record (EMR) the occurrence of a calibration toinform the user of the system's activity.

BRIEF DESCRIPTION OF THE DRAWINGS

The features and advantages of the present invention will be more fullyunderstood with reference to the following, detailed description whentaken in conjunction with the accompanying figures, wherein:

FIGS. 1A-1B illustratively depict exemplary systems, which includeexemplary catalytic type electrochemical gas sensors, for deliveringtherapeutic nitric oxide gas to a patient, in need thereof, inaccordance with exemplary embodiments of the present invention;

FIG. 2A illustratively depicts an exemplary three terminal catalytictype electrochemical gas sensor, in accordance with exemplaryembodiments of the present invention;

FIG. 2B illustratively depicts an exemplary four terminal catalytic typeelectrochemical gas sensor, in accordance with exemplary embodiments ofthe present invention;

FIG. 3 illustratively depicts an exemplary two-point linearinterpolation calibration line, in accordance with exemplary embodimentsof the present invention;

FIGS. 4-9 illustratively depict exemplary drifts of exemplary catalytictype electrochemical gas sensors in exemplary systems for deliveringtherapeutic nitric oxide gas to a patient, in accordance with exemplaryembodiments of the present invention; and

FIG. 10 illustratively depicts an exemplary flowchart for an exemplaryset dose change response algorithm for use with exemplary systems fordelivering therapeutic nitric oxide gas to a patient, in accordance withexemplary embodiments of the present invention.

DETAILED DESCRIPTION

The present invention generally relates to systems and methods forcompensating long term sensitivity drift of electrochemical gasconcentration sensors used in a controlled environment such as insystems for delivering therapeutic nitric oxide (NO) gas to a patient.To compensate for long term sensitivity drift of electrochemical gassensors used in systems delivering therapeutic NO gas to a patient,systems and methods of the present invention, at times, use acalibration process that factors in changes in the set dose of NO beingdelivered to the patient. Factoring in changes in the set dose of NObeing delivered to the patient, the calibration process can initiate aplurality of baseline calibrations of the electrochemical gas sensorwhere the frequency of the baseline calibrations are, at times, based onthe magnitude of the concentration change of the set dose (i.e., theabsolute change in concentration from an initial set dose to a final setdose). This can result in compensation of sensitive changes in theelectrochemical gas sensor.

This long term sensitivity drift may be specific to the sensors atypicaluse because, for example, the sensor can be exposed to the substantiallyhigh NO concentrations (e.g., an order of magnitude more than seenduring typical use) and/or this exposure can be for substantially longdurations of time (e.g., several orders of magnitude longer than duringtypical use) such as when the sensor undergoes continuous duty operationassociated with inhaled NO therapy. Additionally, the sensor may besubjected to localized effects such as, but not limited to, temperaturechanges, chemical changes, humidity, electrolyte conductivity, and/orchanges in physical internal resistance, to name a few. Accordingly,systems and methods of the present invention compensate for this longterm drift that may be specific to the sensor being used in an atypicalmanner, for example, using, amongst other things, calibration processes.

Further, systems and method of the present invention can factor inactions occurring at the therapeutic NO gas delivery system and/oraspects of the surrounding environment prior to performing a baselinecalibration and, in at least some instances, can respond accordingly. Inat least some instances, this can result in postponing of a baselinecalibration and/or rejected using the sensor's output for the baselinecalibration.

Delivery and Sampling System Overview

Referring to FIGS. 1A-1B, exemplary therapeutic gas delivery systems(e.g., which include an electrochemical gas sensor), for deliveringtherapeutic gas to a patient are illustratively depicted. It will beunderstood that catalytic type electrochemical gas sensors and/or anyteachings of the present invention can be used in any applicable systemfor delivering therapeutic gas to a patient. For example, systems andmethods of the present invention can use, modify, and/or be affiliatedwith the delivery systems and/or other teachings of U.S. Pat. No.5,558,083 entitled “NO Delivery System” and/or U.S. Pat. No. 5,752,504entitled “System for Monitoring Therapy During Calibration”, thecontents of both of which are incorporated herein by reference in theirentireties.

The electrochemical gas sensors, systems for delivering therapeutic gasto a patient, and systems and methods are, at times, described as beingdirected towards NO. For example, the electrochemical gas sensor is, attimes, described as a nitric oxide sensor, NO sensor, or the like; thetherapeutic gas delivery system is, at times, describes as a therapeuticnitric oxide delivery system, therapeutic NO delivery system, nitricoxide delivery system, NO delivery system, or the like; and/or thetherapeutic gas is, at times described as nitric oxide, NO, or the like.This is merely for ease and is in no way meant to be a limitation. Ofcourse the teachings disclosed herein can, when appropriate, be used forother therapeutic gas.

In exemplary embodiments, a therapeutic gas delivery system 100 can beused to deliver therapeutic gas, such as NO, to a patient 102 who may beusing an assisted breathing apparatus such as a ventilator 104 or otherdevice used to introduce therapeutic gas to the patient, for example, anasal cannula, endotracheal tube, face mask, or the like. For ease,systems and methods of the present invention are described, at times, asbeing for use with a ventilator. This is merely for ease and is in noway meant to be a limitation. Therapeutic gas can be supplied from atherapeutic gas source 103. Therapeutic gas source 103 can be any sourceof therapeutic gas such as a therapeutic gas contained in a cylinder(e.g., a cylinder containing NO), NO gas generator, or the like. Ofcourse other sources of therapeutic gas can be used.

Therapeutic gas delivery system 100 can include, amongst other things, agas delivery subsystem(s) 105 and/or a gas sampling system(s) 106.Therapeutic gas delivery system 100 can also include user inputinterface(s) 107(a) and/or display(s) 107(b), which may be combined,that can include a display and a keyboard and/or buttons, or may be atouchscreen device. User input interface 107(a) and/or display 107(b)can receive desired settings from the user, such as the patient'sprescription (in mg/kg ideal body weight, mg/kg/hr, mg/kg/breath,mL/breath, cylinder concentration, delivery concentration or set dose,duration, etc.), the patient's age, height, sex, weight, etc. User inputinterface 107(a) and/or display 107(b) can in at least some instances beused to confirm that the desired patient dosing (e.g., user inputdesired dose of NO PPM) using a gas sampling system 106.

It will be understood that any of the elements of system 100 can becombined and/or further separated. For ease elements are, at times,described as being specific to subsystems. This is merely for ease andis in no way meant to be a limitation.

To at least deliver desired set doses of therapeutic gas to a patientand/or sample therapeutic gas being delivered to a patient, therapeuticgas delivery system 100 can include a system controller that maycomprise one or more processors and memory, where the system controllermay be for example a computer system, a single board computer, one ormore application-specific integrated circuits (ASICs), or a combinationthereof. Processors can be coupled to memory and may be one or more ofreadily available memory such as random access memory (RAM), read onlymemory (ROM), flash memory, compact/optical disc storage, hard disk, orany other form of local or remote digital storage. Support circuits canbe coupled to processors, to support processors, sensors, valves,sampling systems, delivery systems, user inputs, displays, injectormodules, breathing apparatus, etc. in a conventional manner. Thesecircuits can include cache memory, power supplies, clock circuits,input/output circuitry, analog-to-digital and/or digital-to-analogconvertors, subsystems, power controllers, signal conditioners, and thelike. Processors and/or memory can be in communication with sensors,valves, sampling systems, delivery systems, user inputs, displays,injector modules, breathing apparatus, etc. Communication to and fromthe system controller may be over a communication path, where thecommunication path may be wired or wireless, and wherein suitablehardware, firmware, and/or software may be configured to interconnectcomponents and/or provide electrical communications over thecommunication path(s).

The clock circuits may be internal to the system controller and/orprovide a measure of time relative to an initial start, for example onboot-up. The system may comprise a real-time clock (RTC) that providesactual time, which may be synchronized with a time-keeping source, forexample a network. The memory may be configured to receive and storevalues for calculations and/or comparison to other values, for examplefrom sensor(s), pumps, valves, etc.

In exemplary embodiments, the memory may store a set ofmachine-executable instructions (or algorithms), when executed byprocessors, that can cause the sampling system and/or delivery system toperform various methods and operations. For example, the delivery systemcan perform a method to, for example, deliver a desired set dose oftherapeutic gas (e.g., NO concentration, NO PPM, etc.) to a patient inneed thereof comprising: receiving and/or determining a desired set doseof therapeutic gas to be delivered to a patient, for example, that maybe input by a user; measuring flow in the inspiratory limb of a patientbreathing circuit; delivering therapeutic gas containing NO to thepatient during inspiratory flow; monitoring inspiratory flow or changesin the inspiratory flow; and varying the quantity (e.g. volume or mass)of therapeutic gas delivered in a subsequent inspiratory flow.

For another example, the sampling system can perform a method to, forexample, determine the concentration of target gas (e.g., NO) beingdelivered to a patient comprising: actuating a sampling pump and/oropening a gas sampling valve (e.g., three way valve, etc.) to obtain agas sample from the inspiratory limb of a patient breathing circuit, thegas sample being of blended air and therapeutic gas (e.g., NO) beingdelivered to a patient; exposing the gas sample to gas sensors (e.g.,catalytic type electrochemical gas sensors); obtaining information fromthe sensor indicative of the concentration of target gas (e.g., NO,nitrogen dioxide, oxygen) being delivered to the patient; communicatingto the user the concentration of the target gas.

For another example, the sampling system can perform a method to, forexample, perform calibrations (e.g., baseline calibrations) of the gassensor (e.g., catalytic type sensor, electrochemical gas sensor, NOsensor, etc.) comprising: actuating a sampling pump and/or opening a gassampling valve (e.g., three way valve, etc.) to obtain a gas sample ofambient air (e.g., conditioned room air); exposing the gas sample ofambient air to gas sensors (e.g., catalytic electrochemical NO gassensors); obtaining information from the sensor indicative ofconcentration of target gas (e.g., NO) in the ambient air (e.g., 0 PPMNO); and generating a new calibration line and/or modifying an existingcalibration line by, for example, replacing the initial and/or previousinformation indicative of zero concentration target gas (e.g., 0 PPM NO)with the obtained information indicative of zero PPM target gas andusing the slope of the initial and/or previous calibration line (e.g.,slope of initial and/or previous calibration line connecting the initialand/or previous zero and span calibration points). Themachine-executable instructions may also comprise instructions for anyof the other methods described herein.

For another example, the sampling system can perform a method to, forexample, select a source of gas having a zero concentration of thetarget gas, which may be ambient air at substantially similar humidityand temperature as the gas from the breathing circuit.

Delivery Sub System Overview

Gas delivery subsystem 105 can include, but is not limited to, adelivery gas pressure sensor(s) 109; delivery flow control valves 111,113, and 115; a delivery gas flow sensor(s) 117; delivery gas flowrestrictor(s) 119; memory(s) 143; and a processor(s) 145.

In exemplary embodiments, gas delivery subsystem 105 can delivertherapeutic gas, at a desired set dose (e.g., a desired concentration),to a patient. For example, gas delivery subsystem 105 can wild streamblend therapeutic gas (e.g., NO, etc.) into patient breathing gas inbreathing circuit 126, affiliated with ventilator 104, as a percentageof the patient breathing gas. To at least wild stream blend therapeuticgas (e.g. NO, etc.) into patient breathing gas, gas delivery subsystem105 can include and/or receive NO from a NO source 103, for example, viaa delivery line 121 that can also be in fluid communication with aninjector module 123, which in turn can also be in fluid communicationwith the inspiratory limb of breathing circuit 126 affiliated withventilator 104.

As used herein, “wild stream blended proportional”, “wild streamblending”, and the like, relates to stream blending, where the main flowstream is an uncontrolled (unregulated) stream that is referred to asthe wild stream, and the component being introduced into the wild streamis controlled as a percentage of the main stream, which may typically beblended upstream (or alternatively downstream) of the main streamflowmeter. In various embodiments, the inspiratory flow may be the “wildstream” as the flow is not specifically regulated or controlled, and thenitric oxide is the blend component that is delivered as a percentage ofthe inspiratory flow through a delivery line.

Ventilator 104 can deliver breathing gas to patient 102 via inspiratorylimb 127 of patient breathing circuit 126, while patient expiration canflow via an expiratory limb 129 of patient breathing circuit 126, attimes, to ventilator 104. With injector module 123 coupled toinspiratory limb 127 of breathing circuit 126, NO can be delivered fromgas delivery subsystem 105 to injector module 123, via delivery line121. This NO can then be delivered, via injector module 123, intoinspiratory limb 127 of patient breathing circuit 126 affiliatedventilator 104 being used to deliver breathing gas to a patient 102.

To regulate flow of NO through delivery line 121 to injector module 123,and in turn to a patient 102 receiving breathing gas from inspiratorylimb 127 of patient breathing circuit 126, therapeutic gas deliverysystem 100 can include one or more flow control valves 111, 113, and 115(e.g., proportional valves, binary valves, etc.). For example, with flowcontrol valves 111, 113, and/or 115 open, NO can be delivered to patient102 by flowing through delivery line 121 to injector module 123, and inturn into inspiratory limb 127 of patient breathing circuit 126 and topatient 102.

In at least some instances, NO delivery system 100 can include one ormore therapeutic gas flow sensors 117 that can measure the flow oftherapeutic gas through flow control valves 111, 113, and 115 and/ordelivery line 121, in turn enabling measurement of the flow oftherapeutic gas to injector module 123, and in turn to patient 102.Further, in at least some instances, injector module 123 can include oneor more breathing circuit gas (BCG) flow sensors 131 that can measure,and communicate to the delivery system, the mass and/or volume flowrate(s) of at least patient breathing gas in the inspiratory line of thebreathing circuit passing through injector module 123, and in turn topatient 102. Although shown as being at injector module 123, BCG flowsensor 131 can be placed elsewhere in the inspiratory limb 121, such asupstream of the injector module 123. Also, instead of receiving flowinformation from BCG flow sensor 131, the delivery system may receiveflow information directly from the ventilator 104 indicating the flow ofbreathing gas from ventilator 104.

In exemplary embodiments, therapeutic gas flow (e.g., NO gas flow) canbe wild stream blended proportional (also known as ratio-metric) to thebreathing gas (e.g., air) flow to provide a desired set doseconcentration of the therapeutic gas (e.g., NO) in the combinedbreathing gas and therapeutic gas. For example, a user can input adesired set dose and the delivery system can deliver this set dose topatient 102. Further, NO delivery system 100 can execute, for example,using machine-executable instructions, a delivered concentrationcalculation that confirms that the desired concentration of thetherapeutic gas (e.g., NO) is in the combined breathing gas andtherapeutic gas using the known concentration of therapeutic gas source103; the amount of breathing gas flow in the patient circuit usinginformation from BCG flow sensor 131 and/or from ventilator 104; and theamount of therapeutic gas flow in delivery line 121 to injector module123 (and in turn to patient 102) using information from therapeutic gasflow sensor 117.

In exemplary embodiments, therapeutic gas delivery system 100 can allowa user to input a desired set dose of the therapeutic gas (e.g., NO inPPM) and the therapeutic gas delivery system can confirm that thedesired set dose of the therapeutic gas is being delivered to thepatient by calculating the delivery concentration (e.g., as describedabove) as well as using gas sampling system 106 to confirm the desiredset dose of the therapeutic gas (e.g., NO) is being delivered to thepatient. In some instances a problem may arise where the sensor does notaccurately report the dose of therapeutic gas being delivered to thepatient.

Gas Sampling Sub System Overview

Gas sampling system 106 can include, but is not limited to numeroussensors such as, but not limited to, an electrochemical NO gas sensor108, which may have a catalytic type electrode material with highcatalytic activity for the electrochemical reactions of the sensor, acatalytic type electrochemical nitrogen dioxide gas sensor 110, and agalvanic type electrochemical oxygen gas sensor 112, to name a few; asample gas flow sensor(s) 114; a sample pump(s) 116; sample systemvalve(s) 118; a processor(s) 120; and memory(s) 122. Sensors 108, 110,and 112 can be in series and/or parallel and/or can be in any order. Forease, sensors 108, 110, and 112 are illustratively depicted as being inseries. This is merely for ease and is in no way meant to be alimitation. In various embodiments, the NO sensor may be anelectro-chemical sensor, which may comprise two electrodes, including asensing and a counter electrode, separated by a thin layer ofelectrolyte.

In exemplary embodiments, gas sampling subsystem 106 can sample and/ormeasure the concentration of various gases being delivered to a patient.The concentration of NO being delivered to patient 102 can be sampledand exposed to NO sensor 108, which in turn can output informationindicative of the concentration of NO in the breathing gas (e.g., NOPPM). For example, a sample of the gas being delivered to the patientcan be sampled via a sample line 124 that is in fluid communication withinspiratory line 127 of breathing circuit 126 affiliated with breathingapparatus 104. This gas sample from inspiratory line 127, via sampleline 124, can flow and/or be pulled to the gas sensors (e.g., NO sensor108). Flow in sample line 124 can be regulated via valve 118 and/orsample pump 116. Sample line mass or volume flow can be measured usingflow sensor 114. Sample line 124 can also be in fluid communication witha gas sample conditioner 128 that may condition the sample gas, forexample, by extracting fluids, placing the sample at the appropriatehumidity, removing contaminants from the sample, and/or can conditionthe sample gas in any other way as desired.

In exemplary embodiments, gas sampling system 106 can performcalibrations (e.g., baseline calibrations, span calibrations, etc.) ofthe gas sensor (e.g., catalytic type electrochemical gas sensor) bysampling and/or measuring the concentration of target gases in acontrolled sample (e.g., baseline sample, span sample, etc.), where aspan sample is a target gas (i.e., nitric oxide) with a specific knownand controlled concentration within a range of interest (e.g., 10 PPM,25 PPM, 50 PPM, 80 PPM, etc.) and/or where a baseline sample is a gascontaining zero concentration of a target gas (i.e., conditioned ambientair containing zero nitric oxide). For example, a sample of ambient gas130 and/or span gas 132 can be sampled via a sample line 134. This gassample from ambient gas 130 and/or span gas 132, via sample line 134,can flow and/or be pulled to the gas sensors (e.g., NO sensor 108). Flowin sample line 134 can be regulated via valve 118 (e.g., a three wayvalve, etc.) and/or sample pump 116. Sample line flow can be measuredusing flow sensor 114.

In exemplary embodiments, sample line 134 can also be in fluidcommunication with a gas sample conditioner 136 that may condition thesample gas, for example, by extracting fluids, placing the sample at theappropriate humidity, removing contaminants from the sample, and/or cancondition the sample gas in any other way as desired. For example, theambient air (e.g., ambient gas 130) used for the baseline calibrationmay be scrubbed of any undesirable gases using a scrubber material. Byway of example, this scrubbing material can be an inline Potassiumpermanganate scrubber material capable of scrubbing the ambient airremoving NO and NO₂. With the NO and NO₂ removed from the ambient air,the scrubbed air can be used for a zero calibration as these undesirablegases have been removed hence they are at 0 PPM. If needed, a similartechnique (e.g., using an inline scrubber material) can be done for spangas.

Sensor Overview

In exemplary embodiments, the electrochemical gas sensor used intherapeutic gas delivery system 100 can be a three terminal catalytictype electrochemical gas sensor and/or a four terminal catalytic typeelectrochemical gas sensor. An exemplary three terminal catalytic typeelectrochemical gas sensor 200 is illustratively depicted in FIG. 2A andan exemplary four terminal catalytic type electrochemical gas sensor200′ is illustratively depicted in FIG. 2B. Generally speaking, boththree and four terminal catalytic type electrochemical gas sensorsinclude a sensing electrode 202 (anode or working electrode) and acounter electrode 206 (cathode) separated by a layer of electrolyte 208.Further, these sensors can also include a capillary diffusion barrier210 that can be used to control the gas reaction rate in the sensor(e.g., reacting with the sensing electrode) and/or a hydrophobic barrier212 that can be used to prevent aqueous liquid electrolyte from leakingfrom the sensor or drying out from lost water vapor. In use, gas flowinginto the sensor passes through a capillary diffusion barrier 210,diffuses through a hydrophobic barrier 212, and subsequently reaches andreacts with sensing electrode 202. The gas sensor can be exposed tosamples of the therapeutic gas, the ambient gas, and/or the span gas.

Gas that reaches sensing electrode 202 reacts at the surface of sensingelectrode 202 by an oxidation or reduction mechanism catalyzed by theelectrode materials specifically selected for the gas of interest. Inother words, when oxidation occurs at sensing electrode 202 (anode)reduction occurs at counter electrode 206 (cathode) and a current can becreated as the positive ions flow to the cathode and the negative ionsflow to the anode. Gases such as oxygen, nitrogen dioxide, and chlorinewhich are electrochemically reducible can be sensed at the cathode whilethose which are electrochemically oxidizable such as carbon monoxide,NO, and hydrogen sulfide can be sensed at the anode. Connecting aresistor and/or current to voltage amplifier 214 across the electrodes(sensing electrode 202 and counter electrode 206), an electrical currentproportional to the gas concentration flows between the anode and thecathode (sensing electrode 202 and counter electrode 206). This currentcan be measured to determine the gas concentration. Because a current isgenerated in the process, these sensors can be described as anamperometric gas sensor, a micro fuel cell, and/or the like, to name afew.

In some instances, electrochemical sensor 200 can also include a thirdelectrode (e.g., a three terminal electrochemical sensors), asillustrated in FIG. 2A, that can act as a reference electrode 216. Inelectrochemical sensors that include a reference electrode, sensingelectrode 202 can be held at a fixed potential relative to the referenceelectrode (from which no current is drawn) so both the referenceelectrode and the sensing electrode maintain a substantially constantvoltage potential (e.g., maintained by a counter current source). Thisconstant electrical potential ensures target gas selectivity orprevention of cross-sensitivity to other non-target gases.

In further instances, electrochemical sensor 200 can include a fourthelectrode (e.g., a four terminal electrochemical sensor), as illustratedin FIG. 2B, that can act as an auxiliary electrode 218. This auxiliaryelectrode 218 can be used to subtract output sensitivity changes notrelated to the concentration of the target gas that may be due to localeffects on electrochemical sensor 200.

An electrochemical sensor 200 may be wired or installed in a suitablesocket, where the wiring or socket may provide for or allow detection ofthe number of electrodes (e.g., by the presence or absence of a voltageor current to or from the electrode.

Sensor Drift

In exemplary embodiments, catalytic type electrochemical gas sensors(e.g. NO sensors, three terminal electrochemical sensors, four terminalelectrochemical sensors, etc.) operate by reacting with the gas ofinterest (e.g., target gas, NO, etc.) thereby producing an electricalcurrent that is, generally speaking, proportional to the concentrationof the gas of interest. For example, the greater the concentration of NOthat reacts with the NO sensor the greater the electrical currentproduced by the sensor. Hence, using this proportional relationship, theelectrical current produced by the sensor can be used to determine theconcentration of the NO gas being sampled and/or delivered to thepatient.

Following the example of delivering therapeutic NO gas, using the outputfrom the NO sensor the concentration of NO can be determined andprovided to a user, for example, on the user display. This can allow theuser to confirm that the set dose (e.g., desired concentration of NO) isactually being delivered to the patient. As noted above, theconcentration of therapeutic gas (NO) in the inspiratory flow beingdelivered to the patient can be calculated, for example, using deliveredconcentration calculation; however, at times, this calculatedconcentration of therapeutic gas may not be displayed to the user.Accordingly, output from the NO sensor may be the only, or preferred,way for the user to confirm the correct therapeutic dose is actuallybeing delivered to the patient, drift in the NO sensor can beparticularly problematic.

Another challenge specific to therapeutic gas delivery, that is notpresent for conventional use of catalytic NO sensors (e.g. smokestackemission monitoring), is that sample flow rates from the breathingcircuit must be kept to a minimum as to not interfere with theventilation therapy (e.g. less than 250 ml/min, which may sometimes beless than the minimum value specified by the electrochemical cellmanufacturer). Gas sample flow rates can appear as leaks in the circuitfrom the perspective of ventilation therapy (e.g. the ventilator). Whenthe therapeutic NO gas monitor is sampling from the breathing circuit,the reported ventilator inspiratory flows (and volumes) are greater thanthe measured expiratory flows (and volumes). This is referred to asinspiratory/expiratory volume mismatch—the patient may not receive thespecified tidal volume. For ventilators with spontaneous ventilationmodes (e.g. actively detect and support patient's inhalation effort) gassample flow rates may interfere with breath detection algorithms and/orbreath detection sensitivity. These ventilators monitor expiratory flowsless than inspiratory flows to detect breaths. When a gas sample flowrate is being drawn from the inspiratory limb of a breathing circuit theresult is that the expiratory flow will measure to be less than theinspiratory flow. All of the effects described above can both have animpact on the patient's ventilation therapy as well as lead to confusionfor the caregiver.

Referring to FIGS. 1A-1B and 3, because of this proportional (nearlinear) relationship, a two-point linear interpolation calibration line300 can be established where a range of electrical output from thesensor corresponds to a range of gas concentrations, including 0 PPMconcentrations. This calibration line can be established by exposing NOsensor 108 to two known gas sources, such as, one containing zero targetgas such as ambient source 130 and span source 132 containing a knownconcentration of target gas. For ease, ambient source 130 and spansource 132 are depicted as being in fluid communication with sample line134. This is merely for ease and is in no way meant to be a limitation.For example, ambient source 130 and/or span source 132 can be in fluidcommunication with sample line 124. Using ambient source 130, an initialbaseline signal (also known as “base current”) calibration point 302 canbe determined by exposing NO sensor 108 to ambient source 130 (e.g.,conditioned ambient that can have 0 PPM of NO and/or that can beinclusive of environmental temperature and humidity) to establish anoutput current for a zero concentration of a target gas of interest(e.g., approximately 4.5 micro-amps output current for 0 PPM of NO).Using span source 132, a span calibration point 304 can be determined byexposing NO sensor 108 to span source 132 (e.g., calibration gas) toestablish an output current for another known concentration (spanconcentration) of a target gas of interest (e.g., approximately 17micro-amps output current for 50 PPM of NO). Connecting span point 304and zero point 302, a linear calibration line 300 for the sensor can beestablished so a user can determine the concentration of gas based onthe output current of NO sensor 108. Of course additional points can bedetermined using a similar technique and/or other known techniques canbe used to produce a reference calibration line. The output values ofthe sensor(s) for the different calibration points may be stored inmemory.

The linear calibration line 300 may be stored in memory as an interceptvalue for the zero point 302 and a slope calculated from the zero pointand span point 304, or as a set of values from multiple span points 304of different concentrations and a zero point 302.

However, during long periods of continuous use, drift (offset) in theoutput current established during the initial calibration line (e.g.,initial baseline calibration, base current, initial span calibration,etc.) can occur. In at least some instances, drift can occur because,amongst other things, the catalytic type electrochemical cell becomessaturated. Drift can cause the output displayed to the user, forexample, in display 107(b) to be incorrect. In turn, the user may not beable to confirm that the desired set dose is actually being delivered tothe patient. This can lead to numerous problems and confusion. Forexample, with an incorrect quantity shown in display 107(b) the user maybelieve the incorrect concentration shown in display 107(b) is theactual concentration being delivered to the patient. Based on thisincorrect information the user may adjust set dose (e.g., NO PPM) andthereby the concentration (e.g., of NO) being delivered to the patient.In turn, this new adjusted concentration could be an incorrect dosagefor the patient even though the displayed dosage may indicate that thequantity being delivered to the patient is the desired set quantity.

Desaturation

To correct for this drift, the sensor can be exposed for an extendedperiod of time (e.g., hours, 24 hours, etc.) to ambient air and/or asource containing zero concentration of the target gas thereby allowingthe sensor to de-saturate. As the sensor slowly de-saturates theoriginal sensor sensitivity slowly returns. After de-saturating, theoriginal calibration line most often can be used and, in some instances,a new baseline calibration and span calibration can be performed togenerate a new calibration line. Although de-saturating the sensor maybe used to correct drift the extended period of time needed tode-saturate the sensor may not be acceptable for an NO sensor used in atherapeutic gas delivery system because, for example, the sensor will beoffline during the de-saturation period.

Zero and Span Calibration

In exemplary embodiments, unlike de-saturating the sensor, to compensatefor drift a baseline calibration and/or a span calibration can beperformed when the sensor is still at least partially saturated. Usingthis output from the baseline calibration and/or span calibration, a newcalibration line that compensates for drift can be generated while thesensor is still at least partially saturated. To perform a spancalibration the sensor needs to be exposed to a span source (e.g., atank containing a known concentration of the target gas, a 50 PPMcanister of NO gas, etc.) and to perform a baseline calibration thesensor needs to be exposed to a source containing zero target gas (e.g.,ambient air containing no target gas).

Conducting a span calibration can be more labor intensive than abaseline calibration as it requires a container having a knownconcentration of the target gas whereas a baseline calibration can useambient air (e.g., conditioned ambient air). In light of at least theabove, it can be more desirable to perform a baseline calibration to,amongst other things, reduce complexity of the system, reduce thefootprint associated with the device (e.g., in areas where critical caremay be needed, in areas where the footprint may be costly or of concern,etc.), and/or ease use of the system. Accordingly, in exemplaryembodiments, to compensate for baseline drift, automatically and/ormanually, a baseline calibration can be performed to generate a newcalibration line that compensates for drift in the electrochemicalsensor, for example, when the sensor is at least partially saturated.

In exemplary embodiments, a new calibration line that compensates fordrift of the at least partially saturated sensor can be generated usingthe sensor output for a new baseline calibration and the slope of theinitial and/or previous calibration line. The sensor drift can be thedifference in the output from the new baseline calibration 306 and theinitial and/or previous baseline calibration 302. By way of example, thequantity of this drift (offset) from the initial baseline current 302(4.5 microamps for 0 PPM of NO) to a new baseline current 306 (−1.0microamp for 0 PPM of NO) can be determined when exposing the sensor to0 PPM of NO (e.g., conditioned ambient air). Applying the initial and/orprevious calibration line's slope to the new baseline current a newcalibration line 308 can be generated. This new calibration line thatcompensates for drift can then be used to determine the concentration oftarget gas (NO) being delivered to the patient.

In exemplary embodiments, reducing the duration of time it takes toperform a calibration (e.g., performed in the calibration scheduledescribed below in greater detail) can be important because it canminimize the time that the monitoring system is offline as, in at leastsome instances, at least some gas concentration alarms (low/high NOalarms, low/high O₂ alarms, high NO₂ alarms, etc.) can be inactiveduring this time. At least some alarms may be inactive during baselinecalibration to prevent false and/or nuisance alarms. Accordingly, inexemplary embodiments, the time to perform a baseline calibration and/ortime offline can include both the response time of the catalytic typeelectrochemical sensor required to obtain the zero offset reading (e.g.,the output indicative of 0 PPM when the sensor may be at least partiallysaturated) and the response time of the catalytic type electrochemicalsensor back to the set dose (e.g., time required for sensor to providethe concentration of the target gas when re-exposed to the target gas atthe set dose). At the time the calibrations are being performed and/orthe alarms are off-line, an indicator may be provided to a user toinform them that calibration is being performed and/or the alarms arecurrently off-line, so users do not come to a mistaken conclusion thatthe system is not functioning properly.

In exemplary embodiments, the quantity of this drift (offset) in thebaseline (zero) current output can be determined by exposing the sensor(e.g., NO sensor) to a known 0 PPM concentration of the gas of interest(e.g., NO), for example, using room air for a period of time (e.g., 3minutes, etc.), where the period of time may be in the range of about 3to 5 minutes to re-establish zero (e.g., within the therapeutic gasdelivery system calibration line) and, after this period of exposure(e.g., to ambient air), the sensor may then require another period oftime (e.g., 2 minutes, etc.), where the period of time may be in therange of about 1 to 2 minutes to stabilize to target gas. This drift canthen be used to adjust the calibration line offset. By way of example,to determine the quantity of this drift (offset) in the initial baselinecurrent output (4.5 micro amps for 0 PPM of NO), a new baseline current306 (−1.0 micro amp for 0 PPM of NO) can be determined when exposing thesensor to 0 PPM of NO (ambient air). The now known baseline currentshift (e.g., from 0 micro amps to −1 micro amps for 0 PPM of NO) can beapplied with the slope of the initial and/or previous calibration lineto report the actual NO gas concentration. In various embodiments, thecalibration may take a period of time in the range of about 4 to 7minutes and/or the system may be offline less than 10 minutes.

In exemplary embodiments, the period of time that the sensor is exposedto a known 0 PPM concentration (e.g., room air) can be determined and/orbased on variables such as, but not limited to, the reaction rate of thesensor to the target gas (e.g., reaction rate of the sensor with air,reaction rate of the sensor with NO, etc.); the physical device size;cell gas exchange rates; thermal impedance to surrounding environment;humidity; sample gas flow rate (e.g., which can be secondary), forexample, which may affect output signal rise and fall times; and/or anycombination or further separation there of; to name a few. In variousembodiments, a gas sensor may be exposed to a gas for about 5 seconds toabout 15 seconds, or about 5 seconds to about 10 seconds to obtain areading.

In exemplary embodiments, the output of a sensor, which may be inmicroamps, may be converted to a digital value (referred to as counts)by an analog-to-digital converter circuit. The rate of change of the NOsensor output can be monitored and compared against predeterminedthresholds deemed “stable”. To determine if the sensor output is stable,the sensor output may be monitored and/or recorded over a period oftime, and the average, minimum, and maximum vales observed during themonitoring period compared to determine how much the sensor output hasvaried and/or how uniform the sensor output was over the monitoredand/or recorded over a period of time, for example, ADC (Analog toDigital) count per unit time, may be 1.5 to 2.5 ADC counts per 10seconds. The ADC counts may have a sampling rate (e.g., 10 measurementsper second), and may be sampled over a set period of time (e.g., 10seconds). For example, a current in microamps may be converted to arelated number of counts in one sampling period of 0.1 second, and thecounts generated over 10 seconds summed and averaged. The number ofcounts measured over a period may be stored in memory. If the sensoroutput (e.g., in microamps or ADC counts) is outside the stablethreshold during the monitoring period, monitoring may be continueduntil the sensor output is within the stable threshold, for example, 1ADC count variation or less over a 10 second monitoring period. It hasbeen found that, in at least some instances, sensor response to changesin concentration of the target gas (e.g., changes in set dose of NO) mayrespond more quickly in newer sensors and/or with smaller absolutechanges in concentration (e.g., smaller absolute changes in set dose).Accordingly, in exemplary embodiments, systems and methods of thepresent invention can adapt to differing rates of change of sensoroutput to minimize duration of time offline. For example, thecalibration schedule and/or set dose change response algorithm,described below in greater detail, can factor in the differing rates ofchange of sensor output to, for example, minimize the duration of timeoffline (e.g., duration of time the NO sensor is offline, etc.). Thesensor signal may exhibit an asymptotic approach to a final value overtime. By monitoring the sensor output for variations over the monitoredand/or recorded over a period of time, the calibration may be concludedwhen the sensor output is within the stable threshold, which may providea value within 99% of the full signal.

In exemplary embodiments, the duration of time the catalytic typeelectrochemical sensor is exposed to ambient air when performingbaseline calibrations, in at least some instances, can be required to bethe same for all baseline calibrations in a calibration schedule. Forexample, all baseline calibrations in the same calibration schedule canbe required to be performed over the same length of time, such that thesensor is exposed to the gas for the same length of time each time acalibration is conducted. For example, the reading from a gas sensor maybe taken at the end of a 5 second exposure time for each baselinecalibration. By taking a reading for the same exposure time each time acalibration is conducted, the sensor has the same period of time torespond and produce the same final value. From research Applicant foundthat when exposing the sensor to room air (e.g., initiating an autocalibration), output from the sensor initially decreases substantiallyrapidly for a short period of time, where the sensor output approaches90% of final value in approximately the first 30 seconds of exposure.The time period may vary based on the responsiveness of the sensor,where the sensor output may approach 90% of the final value inapproximately the first minute or two of exposure, and then the sensoroutput slowly decreases (e.g., exponential decay) to baseline over alonger period of time (e.g., hours of exposure, days of exposure, weeksof exposure, etc.). This later slower decay over a longer period of timecan be the time required for desaturation. However, for driftcompensation of the sensor using baseline calibrations, applicant foundthat this slower decrease in sensor output over a longer period of timemay be less significant (e.g., than the initial substantially rapiddecrease in sensor output) for determining baseline drift compensation.Noting this initial rapid decrease in sensor output, in exemplaryembodiment, the duration of time for exposing the sensor to ambient air(e.g., baseline zero calibrations) can be required to be the same forall, or at least some, of the baseline zero calibration.

Calibration Schedule (Set Dose Change)

Although the baseline calibration may be used to compensate for drift,when using catalytic type electrochemical sensors (e.g., NO sensors) ina therapeutic gas delivery system that delivers the therapeutic gas(e.g., NO) to a patient (e.g., for a prolonged period of time) suchbaseline calibrations can require the signal from the electrochemicalsensor to go offline. As noted above, having the electrochemical sensorgo offline can be problematic. because, for example, when the sensorgoes offline users (e.g., doctors, nurses, etc.) may not be able tomonitor NO delivery and/or modify delivery of NO to a patient. Inaddition, a reading different that the expected set dose or no readingat all may be displayed to a user during this “blackout” period, whichmay cause concern or lead to confusion. Conversely, if the sensor is notre-zeroed (e.g., baseline calibrated, etc.) then the measuredconcentration of NO may not be accurate. The above can be problematicbecause, although it may be preferable from at least an accuracystandpoint to perform baseline calibrations very frequently, frequentbaseline calibrations may not be acceptable from at least a therapeuticstandpoint as the therapeutic gas delivery system's ability to use theelectrochemical sensor goes offline during the baseline calibration. Inat least some embodiments, the electrochemical sensor may be offline fora period of time in the range of 5 min to about 10 min, or for a maximumtime period of 10 minutes during the baseline calibration.

Noting the above, Applicant conducted extensive research and found thatelectrochemical gas cell sensitivity drift can be related to theabsolute change in concentration of the therapeutic gas (e.g., absolutechange in NO set dose) where the larger the absolute change the moredrift occurred. Noting this relationship, the frequency of calibrations(e.g., baseline calibrations, etc.) performed on catalytic typeelectrochemical sensors (e.g., NO sensor) can be reduced by factoring inthe absolute concentration change of NO being delivered to the patient(e.g., the absolute concentration change of the set dose of NO). Hence aschedule (e.g., calibration schedule), that factors in the absoluteconcentration change of NO being delivered to the patient (e.g., theabsolute concentration change of the set dose of NO), can be used toensure greater accuracy of the sensor while reducing the duration oftime and/or quantity of times that the sensor goes offline. Accordingly,in exemplary embodiments, the frequency of baseline calibrations in acalibration schedule can be based on the absolute change inconcentration of NO being delivered to the patient (e.g., absolutechange in set dose) wherein the frequency of baseline calibrations maybe more frequent (e.g., shorter intervals between baseline calibrations)for a greater absolute changes in concentration of NO being delivered tothe patient (e.g., absolute change in set dose) and/or the frequencybaseline calibrations may be less frequent (e.g., longer intervalsbetween baseline calibration) for lesser absolute changes inconcentration of NO being delivered to the patient (e.g., absolutechange in set dose). The interval between calibrations may increaseproportionally with an absolute change in the set dose. The duration ofroom air zeroing or span calibration can be insignificant for changes incell saturation or desaturation.

Referring to FIGS. 4-5, demonstrative graphs illustrate drift in thedesired set dose (e.g., as displayed to the user to confirm an accuratedose of NO is being delivered to a patient) and baseline calibrations,used in an exemplary calibration schedule, of an exemplary four terminalcatalytic type electrochemical NO gas sensor with respect to time for apatient who may actually be receiving the desired set dose. That is, thepatient may be receiving the correct set dose; however, the displayedamount to the user shows the incorrect amount being delivered. Forexample, the demonstrative graph illustrated in FIG. 4 shows drift andbaseline calibrations for a patient receiving a set dose of 50 PPM of NOand the demonstrative graph illustrated in FIG. 5 shows drift andbaseline calibrations for a patient receiving a set dose of 25 PPM ofNO. It will be understood that the dosage to the patient can remain atthe desired set dose (e.g., set dose of 50 PPM NO, set dose of 25 PPMNO, etc.) even though the readout from the sensor may drift (e.g., whichin turn may be displayed to the user of a therapeutic gas deliverysystem as a different PPM being delivered to the patient). In variousembodiments, the type of electrochemical gas sensor may be entered intomemory, for example by a user or by automatic detection of theelectrochemical gas sensor by the system controller. In variousembodiments, the type of electrochemical gas sensor may be detected bymonitoring a potentiostat and detecting a change in voltage and/orcurrent for an electrode, and/or detecting the presence of a current orvoltage at a prong in a socket configured for the sensor.

In exemplary embodiments, a recalibration schedule can be used todetermine when the baseline calibrations occur and/or implemented inresponse to a set dose change, at times automatically. By way ofexample, the patient can begin receiving the set dose of NO at 50 PPM(e.g., as set by the user) thereby exposing the NO sensor to 50 PPM ofNO; however, as shown the sensor begins drifting (e.g., giving anindication that the patient may be receiving a lower PPM dosage thanwhat was set and/or actually being delivered to the patient). To correctthis drift a baseline calibration can be performed on the sensor after adesired amount of time (e.g., three hours, four hours, six hours) ofexposure to NO. This interval may be measured using an internal clock ora real time clock within the system or system controller, wherein theinternal clock or a real time clock may be used to identify a time forexecuting a calibration. After performing a baseline calibration, thesensor can then be exposed to NO again. Subsequently the sensor mayagain begin drifting. To correct this drift a baseline calibration canagain be performed on the sensor after another desired amount of time(e.g., six hours, eight hours, twelve hours) of exposure to NO. Thisinterval may be measured from the previous interval relatively using theinternal clock or absolutely using the real time clock to identify atime for the subsequent calibration. After performing the previousbaseline calibration, the sensor can then resume being exposed to NO at50 PPM and again the sensor may begin drifting. To correct this drift abaseline calibration can be performed on the sensor after yet anotherdesired amount of time (e.g., twelve hours) of exposure to NO. Invarious embodiments, the maximum interval between calibrations may be 24hours, so that a minimum of one calibration is run per day.

In exemplary embodiments, the recalibration schedule(s) may be stored inthe controller memory. There may be one or more recalibrationschedule(s), where a recalibration schedule comprises one or more valuesindicating one or more time intervals between calibration operations. Byway of example, a method of calculating a recalibration schedule may bebased on 150 PPM-hours and include dividing 150 PPM by the set dose todetermine the number of hours of the time interval between calibrationoperations. For example, if after a set dose of 50 PPM for 3 hours, 150PPM-hours would have accumulated. If then, a new dose of 25 PPM was nowset, an accumulation of 6 hours (150 PPM-hours) would occur beforeanother baseline calibration. Subsequent intervals between calibrationsmay be double the earlier interval up to 12 hours, and/or up to 24 hoursthereafter.

In an exemplary embodiment, the PPM-hours (e.g., X PPM-hours) may bedoubled (e.g., 2X PPM-hours) to calculate the interval until the secondcalibration, and doubled again to calculate the interval until the thirdcalibration, etc., until the maximum 24 hour calibration is reached. Byway of example, the 150 PPM-hours may be doubled to 300 PPM-hours tocalculate the interval until the second calibration, and doubled againto calculate the interval until the third calibration, etc., until themaximum 24 hour calibration is reached. For example, a change in setdose from 10 PPM to 60 PPM would produce and absolute change of 50 PPM,so the interval between the set dose change and the first calibrationwould be 150 PPM-hours/50 PPM=3 hours. The next interval would be 300PPM-hours/50 PPM=6 hours after the first calibration, as measured by theclock, followed by an interval of 600 PPM-hours/50 PPM=12 hours later.The following interval would be 1200 PPM-hours/50 PPM=24 hours later,which can also the maximum interval, so no further calculations aredone, and each subsequent interval between calibrations remains 24hours. It has been found that the greatest amount of drift occurs duringthe first 24 hours after a set dose change, and drifts only slightlyover a 24 hour period if the concentration remains the same for thatperiod.

As noted above, in exemplary embodiments, calibration schedules canfactor in the absolute change in the set dose of NO being delivered tothe patient, wherein, larger absolute changes in set dose can requiremore frequent baseline calibrations than smaller absolute changes, wherefor example a positive or negative change of 10 PPM has less of animpact on the interval between calibrations than a positive or negative50 PPM change. By way of example, FIG. 4 illustrates, amongst otherthings, an absolute change from 0 PPM NO being delivered to NO beingdelivered to a patient at 50 PPM (and thereby exposing an exemplary fourterminal catalytic type electrochemical NO gas sensor to 50 PPM of NO),while FIG. 5 illustrates, amongst other things, at least one embodimentfor an absolute change from 0 PPM NO being delivered to NO beingdelivered to a patient at 25 PPM (and thereby exposing the exemplaryfour terminal exemplary catalytic type electrochemical NO gas sensor to25 PPM of NO). As can be seen by comparing FIG. 4 and FIG. 5, for agreater absolute change in concentration NO (e.g., as shown in FIG. 4)the drift is larger and therefor baseline calibrations may be morefrequent than for a lesser absolute change in concentration of NO (e.g.,as shown in FIG. 5). In various embodiments, the value for the number ofPPM-hours may depend on the type of sensor installed and/or detected bythe system controller, or may be set by a user for example. In someembodiments, the system may have a default schedule of auto-calibrationevery 24 hours.

Based upon the calculations using 150 PPM-hours, the 50 PPM changegenerates a first calibration interval of 150 PPM/50 PPM=3 hours, asshown in FIG. 4. Of course other PPM-hours are envisioned. For example,based upon the calculations using 100 PPM-hours, a 25 PPM changegenerates a first calibration interval of 100 PPM/25=4 hours, as shownin FIG. 5.

In exemplary embodiments, the frequency of baseline calibrations in acalibration schedule, which may be based on the absolute change inconcentration of NO being delivered to the patient (e.g., set dose), canalso depend on whether the catalytic type electrochemical sensor hasthree terminals or four terminals. In at least some instances, fourterminal catalytic type electrochemical sensors may have calibrationschedules that initially vary the duration between baseline calibrationsand then have fixed durations between baseline calibrations. In at leastsome instances, three terminal catalytic type electrochemical sensor mayhave calibration schedules having fixed durations between baselinecalibrations.

While not intending to be bound by theory, or to limit the scope of theinvention in any way, it is presently believed that, although theauxiliary electrode in the four terminal catalytic type electrochemicalsensor (e.g., NO sensor) may be intended to be used to cancel outlocalized effects seen on the sensing electrode that may produce and/oreffect output (e.g., electrical current, ADC counts, etc.) from thesensing electrode not indicative of the target gas concentration, whenused atypically the localized effects on the auxiliary electrode and thelocalized effects on the sensing electrode may not be the sameinitially; however, after prolonged exposure (e.g., 24 hours) to thesame concentration NO (e.g., set dose remains constant) this differencebetween the auxiliary electrode and sensing electrode may becomenegligible. In other words, when the set dose changes, for four terminalcatalytic type electrochemical sensors (e.g., NO sensors), there may bean initial period of non-steady state which is then followed by a steadystate period. On the other hand, as a three terminal catalytic typeelectrochemical sensor (e.g., NO sensor) does not include this auxiliaryelectrode this effect does not occur. It is believed that this may bethe reason why, for the same absolute change in NO, differentcalibrations schedules may be needed for three terminal catalytic typeelectrochemical sensors and four terminal catalytic type electrochemicalsensors. These localized effects may include, but are not limited to,temperature changes, chemical changes, humidity, and/or changes inphysical internal resistance from when first reference calibration hasbeen applied to the device (e.g., that may be specific to the sensoratypical use), to name a few.

For example, as illustrated in FIGS. 4-5, along with the intervalsbetween baseline calibrations varying with respect to the absolutechange in set dose, the calibration schedule for a four terminalcatalytic type electrochemical sensor can vary for an initial period oftime and then become fixed. As shown, along with the intervals betweenbaseline calibrations varying with respect to the absolute change in setdose, the intervals between baseline calibrations in the calibrationschedule can initially vary (e.g., 3 hours, 6 hours, 12 hours; 4 hours,8 hours, 16 hours; etc.) and then become fixed (e.g., 12 hours; 16hours; etc.).

For another example, as illustrated in FIGS. 6-7, along with theintervals between baseline calibrations varying with respect to theabsolute change in set dose, the calibration schedule for a threeterminal catalytic type electrochemical sensor can be fixed. As shown,along with the intervals between baseline calibrations varying withrespect to the absolute change in set dose, the intervals betweenbaseline calibrations in the calibration schedule can be fixed (e.g., 3hours; 4 hours; etc.).

It will be understood that the absolute change in the set dose of NOdelivered to the patient refers to the absolute change from zero PPM NO(e.g., prior to delivery of therapeutic NO to the patient) to theinitial set dose of NO and changes in the set dose (e.g., changes in theset dose during treatment). In exemplary embodiments, calibrationschedules that factor in absolute changes in set dose can treat theabsolute change in set dose when first beginning treatment (e.g.,initial set dose) the same as changes in the absolute set dose whichoccur during treatment. For example, the calibration schedule,illustrated in FIG. 8, for a four terminal catalytic typeelectrochemical sensor having an initial set dose of 25 PPM NO (e.g., aabsolute change in set dose of 25 PPM NO) can be the same as thecalibration schedule, as illustrated in FIG. 9, for the same fourterminal catalytic type electrochemical sensor having an change set dosefrom 40 PPM NO to 15 PPM NO (e.g., an absolute change in set dose of 25PPM NO).

In exemplary embodiments, systems and methods of the present inventiondetect changes in the set dose (e.g., initial set dose, changes in setdose during treatment, etc.), determine the absolute change in set dose,and selected and/or implement the appropriate calibration schedule basedon the determined absolute change in set dose. For example, in responseto a user setting an initial set dose (e.g., to 50 PPM) the desiredauto-calibration schedule for that set dose can be selected, forexample, automatically by machine-executable instructions. For anotherexample, in response to a user changing the set dose (e.g., from 75 PPMto 25 PPM; from 25 PPM to 50 PPM; etc.) the desired auto-calibrationschedule for that absolute change in the set dose can selected, forexample, automatically by machine-executable instructions.

Referring to FIG. 10, the therapeutic gas delivery system can perform atleast some of the steps in the exemplary method illustrated to, forexample, automatically implement the appropriate recalibration schedulein response to a set dose change. Table 1 illustrates and exemplary setof recalibration schedules. By way of example, a set dose changeresponse algorithm 1000 stored in memory (memory affiliated with thetherapeutic gas delivery system) can include machine-executableinstructions that processors (processors affiliated (operativelyassociated) with the therapeutic gas delivery system) can access andexecute, for example, in response to a change in set dose. This changein set dose can be the initial set dose and/or a change in set doseduring delivery of the therapeutic gas to a patient. For ease, the belowexample distinguishes the initial set dose change from a set dose changeduring delivery of the therapeutic gas to a patient. This is merely forease and is in no way meant to be a limitation. One of ordinary skill inthe art will recognize that a recalibration schedule can be generated bya formula or an algorithm where applicable.

TABLE 1 Magnitude of Change in Dose Setting (PPM) Interval Time BetweenCalibrations (Hrs) 5 24 24 24 24 24 20 8 12 24 24 24 25 6 12 24 24 24 404 8 12 24 24 50 3 6 12 24 24 80 2 4 8 12 24

At step 1002, an initial set dose can be input (e.g., by the user)and/or an initial set dose value can be stored in memory (memoryaffiliated with the therapeutic gas delivery system controller). As thisis the initial set dose value, at times, the previous set dose value canbe presumed to be zero. In some instances, the user may have previouslybeen receiving a set dose, for example, from another therapeutic gasdelivery system. For such situations, the user may input (e.g., via theuser interface) what the previous set dose (e.g., that was beingdelivered by another therapeutic gas delivery system to the patient) wasand the previous set dose value can be stored in memory (memoryaffiliated with the therapeutic gas delivery system). Also, for suchsituations, if applicable, the therapeutic gas delivery system cancommunicate (e.g., via a communications portal affiliated with thetherapeutic gas delivery system) with the other therapeutic gas deliverysystem (e.g., the previous therapeutic gas delivery system that wasdelivering therapeutic gas to the patient) and the previous set dosevalue (e.g., the previous set dose that was being delivered to thepatient) can be communicated (e.g., via a communications portalaffiliated (operatively associated) with the therapeutic gas deliverysystem) and stored in memory (memory affiliated with the therapeutic gasdelivery system controller).

In exemplary embodiments, an initial auto-calibration may be run toestablish an initial baseline, and to compensate for any drift duringthe time the system may have been off (e.g., during storage,maintenance, change of NO container, etc.). An initial set dose input bya user may then be used to determine the absolute change (i.e., from 0PPM) and the auto-calibration schedule. In situations where the gasdelivery system may be on and running, but have a set dose of 0 PPM, anauto-calibration may be done every 24 hours. During such a period of 0PPM operation, the sensor may become desaturated, thereby requiringcompensation for drift.

In various embodiments, upon boot-up of the therapeutic gas deliverysystem, the system may immediately initiate a default calibration (e.g.,every 24 hours), and begin a baseline calibration after boot-up butbefore a user may be allowed to enter an initial set dose to ensure thatthe sensor is calibrated and an accurate baseline value has been storedin the system controller memory. Such initial calibrations may beperformed to reset the baseline and/or compensate for desaturation whilethe device is in storage, or when the therapeutic gas delivery system ispowered back on after a previous therapy session, and prior to the nexttherapy session.

If a user attempts to run a pre-use checkout during such an automaticbaseline calibration, the system controller initiating the pre-usecheckout can automatically notify the user that they must delay deliveryto the patient and monitoring performance tests until the automaticbaseline calibration and any re-try attempts are complete.

At step 1004, the therapeutic gas delivery system controller candetermine the absolute change in set dose value to, for example,determine if the absolute change in set dose value threshold is met, atstep 1006, and/or select a desired calibration schedule, at step 1008.The absolute change in set dose can be determined by calculating theabsolute value of previous set dose minus the new set dose. For example,processors (processors affiliated with the therapeutic gas deliverysystem) can access the previous set dose value (e.g., NO at 50 PPM, NOat 0 PPM, etc.) and subtract the new set dose (e.g., NO at 25 PPM, NO at40 PPM, etc.) from the previous set dose. This determined absolutechange in set dose can be made positive, if needed. In variousembodiments, the threshold in set dose may be 5 PPM NO to initiate adetermination and/or selection of a recalibration schedule.

At step 1006, the therapeutic gas delivery system controller candetermine if a threshold value (e.g., 5 PPM NO) is met to initiateselection and/or implementation of the desired recalibration schedule.This threshold value can be based on a minimum absolute change in setdose and/or a cumulative amount of set dose delivered (e.g., PPM-hours),where the cumulative amount may be 150 PPM hours. A threshold value forinitiating selection and/or implementation of the desired calibrationschedule may be included in set dose change response algorithm 1000 suchthat if the absolute change in the set dose and/or cumulative set dosedelivery amount is below the threshold then the therapeutic gas deliverysystem may not select and/or implement a new calibration schedule and/ormay store the new set dose value in memory, in the event there is alater change in set dose and/or additional set dose delivered (e.g., toadd to the cumulative amount of set dose delivered). Confirmation thatthe absolute change in set dose is above a threshold (e.g., 5 PPM) maybe done as minor changes in set dose and/or minor cumulative amounts ofset dose delivered may not necessitate selection and/or implementationof a calibration schedule.

For example, absolute changes in set dose that are less than 5 PPM maynot result in substantial drift, therefore a change of 5 PPM or lesswill not initiate a recalculation or redetermination of a recalibrationschedule. For another example, cumulative amounts of set dose deliveredthat are less than 100 PPM hours (e.g., 20 PPM delivered for 5 hours)this may not result in substantial drift. For yet another example,combined cumulative amounts of set dose delivered that are less than 100PPM Hours (e.g., 20 PPM delivered for 5 hours) and absolute changes inset dose that are less than 5 PPM may not result in substantial drift.If the threshold is not met, the therapeutic gas delivery system cantake no action, and, if a set dose change occurs, proceed to step 1012.If the threshold is met, the therapeutic gas delivery system can proceedto selection and/or implementation of an appropriate calibrationschedule.

In exemplary embodiments, at step 1008, processors can then select theappropriate calibration schedule for the determined absolute change insent dose value, for example, from calibration schedules stored inmemory (memory affiliated with the therapeutic gas delivery system)based on the determined absolute change in set dose value.

At step 1010, the therapeutic gas delivery system can implement theselected calibration schedule resulting in baseline calibrations beingperformed (e.g., automatically) at intervals defined by the selectedcalibration schedule. For example, when the selected calibrationschedule is implemented, the sampling system can perform a method to,for example, execute baseline calibrations comprising: actuating asampling pump and/or opening a gas sampling valve (e.g., three wayvalve, etc.) to obtain a gas sample of ambient air (e.g., conditionedroom air); expose the gas sample of ambient air to gas sensors (e.g.,catalytic electrochemical NO gas sensors) for a period of time; obtaininformation from the sensor indicative of concentration of target gas(e.g., NO) in the ambient air (e.g., 0 PPM NO); and generate a newcalibration and/or modify an existing calibration line by, for example,replacing the initial and/or previous information indicative of zero PPMtarget gas with the obtained information indicative of zero PPM targetgas and using the slope of the initial and/or previous calibration line(e.g., slope of initial and/or previous calibration line connecting theinitial and/or previous zero and span calibration points). Thecalibration line may be stored in the controller memory as a zerointercept value from the baseline calibration and a slope from aninitial calibration to provide the values of the formula Y=mx+b, where“m” is the slope and “b” is the zero intercept. The calibration line maybe stored in the controller memory as a table of data point values overthe calibration span including the zero intercept. Changes in the zerointercept determined by baseline recalibrations may then be used tocorrect the equation and/or the stored data points, so they representthe new calibration line.

At step 1012, while therapeutic gas delivery system delivers therapeuticgas to the patient, the therapeutic gas delivery system can monitorand/or detect a change in set dose. For example, the therapeutic gasdelivery system can detect a change in the value of set dose based onuser input changes in the set dose. Of course if no set dose change isdetected the therapeutic gas delivery system can continue to check for aset dose change and/or remain waiting to detect a set dose change. If aset dose change is detected, the therapeutic gas delivery system canperform the steps discussed above at step 1004.

Postponing Calibrations

In one or more embodiments, a calibration may be postponed for a periodof time if an alarm is active at the time the calibration was intendedto take place. The system controller may determine that an alarm isactive and continue to recheck the presence of an alarm and/or delay theinitiation of a calibration operation for a set interval (e.g., that maybegin after the alarm clears) and recheck for the alarm after the setinterval has expired. In embodiments, the system controller may monitorthe alarm and determine when the alarm has been cleared, at which timethe controller may delay an auto-calibration by a predetermined time,for example, to ensure the alarm is not retriggered. In addition, thesystem controller may determine if an alarm was previously activatedwithin a predetermined time period before the calibration is to beexecuted, wherein the calibration may be postponed if the active alarmis detected and executed if the active alarm is not detected. Thecontroller may also monitor the occurrence of other activities and/oroff-line circumstance that may otherwise interfere with auto-calibrationand institute a delay to allow such circumstance to be resolved. Thesystem controller may also detect if a user is interacting or hasinteracted with the therapeutic gas delivery system within apredetermined timeframe at the time the calibration is to be executed,wherein the calibration is postponed if the user is interacting or hasinteracted with the therapeutic gas delivery system within thepredetermined timeframe, and executed if the user is not interacting orhas not interacted with the therapeutic gas delivery system within thepredetermined timeframe.

In one or more embodiments, a calibration may be postponed for a periodof time if the user is interacting with therapeutic gas delivery systemat the time the calibration was intended to take place. Interactions caninclude, but is not limited to, interaction with the user input,changing of the therapeutic gas source, changing the gas sampleconditioner, decoupling the delivery system from a cart affiliated withit, purging, etc. The system controller may determine that the user isinteracting with the delivery system and continue to recheck thepresence of an alarm and/or delay the initiation of a calibrationoperation for a set interval (e.g., after the last interaction ends) andrecheck for user interaction after the set interval has expired.

In one or more embodiments, a calibration may be postponed for a periodof time if the sensor output during a baseline recalibration withambient air indicates the presence of an interfering gas, for exampleH₂S, NO₂, etc. interfering gas that may come from cleaning products,flatulence, a leak in the system, or other contaminant sources. In suchinstances, the recalibration will be interrupted and/or rejected andrescheduled for a time 1, 5, 10, or 15 minutes later to allow theambient air to clear. In at least some instances, postponing acalibration may be required because the new baseline calibration basedon the sensor output during this period of time would not be necessarilybe indicative of the sensors drift and this can lead to the newcalibration line being inaccurate. This can lead to improper dosinginformation being displayed to the user. In at least some instances,this sensor output is rejected ensuring that it is not used forcompensation of drift. In various embodiments, the system controller maydetect if one or more interfering gasses are causing or have causedsensor output to be outside a threshold range within a predeterminedtimeframe at the time the calibration is to be executed, wherein thecalibration is postponed if the sensor output is or has been out ofrange within the predetermined timeframe at the time the calibration isto be executed, and executed if the sensor output is not or has not outof range within a predetermined timeframe. In various embodiments, thesystem controller may detect if one or more interfering gasses arecausing or have caused a postponement of a calibration due to detectionof sensor output outside a threshold range within a predeterminedtimeframe at the time the calibration is to be executed, wherein thecalibration may be postponed again if the sensor output is still out ofrange within the predetermined timeframe at the time the calibration isto be executed, and executed if the sensor output is not out of rangewithin a predetermined timeframe.

In exemplary embodiments, the system controller can determine when aninterfering gas may be effecting the sensor because the sensor outputmay be outside of the range expected due to drift (e.g., 0 ADC counts to655 ADC counts). For example, the system controller can postpone acalibration when the sensor output is greater than an expected outputthreshold. In at least some embodiments, the expected output thresholdcan be 0 ADC counts to 655 ADC counts and when the sensor output isoutside this expected output threshold the system controller canpostpone the calibration a period of time (e.g., 1, 5, 10, or 15minutes). The sensor can then undergo the calibration; however, if thesensor output is again above the expected output threshold thecalibration can again be postponed. This can be repeated as neededthereby ensuring that the interfering gas has dispersed (e.g., allowingthe ambient air to clear).

Calibration Schedules (Quantity)

In exemplary embodiments, there may only be one or a small number ofcalibration schedules stored in memory (memory affiliated with thetherapeutic gas delivery system). A limited number of calibrationschedules may be available for selection to, for example, conserve onmemory usage and/or reduce complexity. For example, in at least someexemplary embodiments, only one calibration schedule may be stored inmemory and/or this calibration schedule may be selected to address thelargest absolute change in set dose seen under the vast majority ofuses. Using this calibration schedule for this set dose (e.g., that isthe largest seen the vast majority of the time) then at step 1008 onlythis schedule may be available for selection. This can be beneficial asmemory usage and/or complexity can be reduced, while a calibrationschedule can be implemented that addresses sensor drift while alsoreducing the quantity and/or duration of times the sensor goes offline.By way of example, as the vast majority (e.g., 99%, etc.) of alldeliveries of therapeutic gas may be less than a set dose of NO at about50 PPM, then using a calibration schedule based on an absolute change inset dose of 50 PPM addresses the worst case scenario as well as providesthe benefit of reduced sensor time offline. Following this example, ifthe absolute set dose change is, for example, 20 PPM the calibrationschedule used may be that for an absolute set dose change of 50 PPM.

Sample Valve

In exemplary embodiments, the above described gas sampling valve (e.g.,valve(s) 118 illustrated in FIGS. 1A-1B) can be a three way valve influid communication with the gas sensors (e.g., NO sensor); the gas inthe breathing circuit (e.g., via sampling line 124 illustrated in FIG.1); and calibration gas such as ambient air, that may be conditioned,(e.g., via sampling line 134 illustrated in FIG. 1). Using a three wayvalve, when the valve is opened in a first position the sensors can beexposed to samples of gas in the breathing circuit, while calibrationgas flow is restricted and when the valve is opened in a second positionthe sensors can be exposed to calibration gas (e.g., ambient conditionedair), while sample gas flow from the breathing circuit is restricted.Utilizing the above configuration, when a baseline calibrations arebeing performed the breathing circuit sample line does not need to bedisconnected from the breathing circuit and/or the therapeutic deliverysystem. Without such configuration users may be required to disconnectthe breathing circuit sample line from the breathing circuit and/or thetherapeutic delivery system, which can be undesirable as, generallyspeaking, modification to the breathing circuit can increase risk ofdamaging the circuit or components affiliated with it, increase risk tothe patient, and/or impact delivery of therapeutic gas to the patient.

In at least some instances, systems and methods of the present inventioncan detect whether the gas sampling valve is functioning properly to,for example, prevent improper calibration. This can be particularlyimportant for baseline calibrations performed automatically as the usermay not be present to observe the gas sensor readings duringcalibration. In exemplary embodiments, the therapeutic gas deliverysystem can detect whether the gas sampling valve is functioning properlyby monitoring the electrical current the sampling valve uses (e.g.,current pulled when actuated, etc.) and/or by monitoring the flow and/orpressure in the sampling lines (e.g., sampling line 134 and/or samplingline 124 illustrated in FIGS. 1A-1B, etc.). For example, the therapeuticgas delivery system can detect whether the gas sampling valve isfunctioning properly by monitoring the pressure and/or flow in the gassample line just upstream of the sample pump as the pressure and/or flowin the line for receiving ambient and/or span samples (e.g., sample line134 illustrated in FIG. 1A) may be different than the pressure and/orflow in the line for receiving samples from the patient breathingcircuit (e.g., sample line 124 illustrated in FIG. 1A). In variousembodiments, the ADC counts just prior to a calibration may be stored intemporary memory for comparison with the ADC counts during the baselinecalibration, where an insignificant change in the ADC counts mayindicate that the valve has not functioned properly. When detected asnot functioning properly the calibration can be postponed, retried,and/or may be cancelled.

User Notification

In exemplary embodiments, the display may be blank during a calibrationto avoid a user misinterpreting such values during a calibration as aset dose reading. To avoid such confusion, a message indicating that acalibration is in effect may be displayed to a user and/or recorded inthe electronic medical record (EMR) to inform a user of the system'sactivity. For example, the user can be informed that the concentrationmonitoring of the inspiratory line 127 of breathing circuit 126 ispresently off-line, for example by a suitable message and/or auditoryindicator.

In exemplary embodiments, alarms for the system may be taken off-line toavoid triggering an alarm due to the discrepancy between the set doseand the concentration be measured by the sensor during the calibration.This may be referred to as an alarm blackout. This alarm blackout mayalso cause confusion for a user that expects an alarm when the measuredconcentration (e.g., displayed to the user) differs from the set dose. Amessage that the alarm(s) have been disabled during the calibrationperiod (e.g., 5 to 10 minutes) may be displayed, so the user is properlyinformed.

In exemplary embodiments, the system may alert the user that acalibration has failed. This may occur if the valve does not functionproperly, or multiple attempts at calibration produce sensor values thatare outside the threshold values, the number of calibration retries(e.g., 4, 5, 6, etc.) before a failure message is displayed may beselected by a user or predetermined and hard-coded into the systemcontroller or stored in memory.

Drift Overview

As mentioned above, while not intending to be bound by theory, or tolimit the scope of the invention in any way, it is presently believedthat although the auxiliary electrode and sensing electrode are intendedto be under nearly identical conditions with the exception that thesensing electrode is exposed to the target gas (e.g., NO) while theauxiliary electrode is not exposed to the target gas, there appears tobe localized effects which may cause the auxiliary electrode and sensingelectrode not, at least for an initial period of time, to be underidentical conditions. These localized effects may include, but are notlimited to, temperature changes, chemical changes, humidity, and/orchanges in physical internal resistance from when first referencecalibration has been applied to the device (e.g., that may be specificto the sensor atypical use), to name a few.

Regarding chemical effects, it is believed that the electrolyte in thecatalytic type electrochemical gas sensor (e.g., NO sensor) may bepolluted by oxides (e.g., oxides of the Nitrogen from the NO), forexample, because the concentration of NO used can be substantiallyhigher than the concentration that these types of sensors may be exposedto conventionally and/or because the duration of exposure of thesesensors when used in therapeutic NO delivery can be substantially longerthan the exposure duration these sensors may have when usedconventionally for toxic gas emission measurements. In at least someinstances, it is believed that this localized effect may be the cause,dominant cause, for sensor drift seen when using the sensor atypically.

Regarding temperature effects, referring back to FIG. 2A, it has beenfound that the baseline signal of three terminal electrochemical sensorsused under continuous duty tends to increase exponentially with time andtemperature (e.g., approximately doubling for every 30° C. rise intemperature). This percentage signal change related to temperaturechange has been found to be similar between the baseline signal outputand for a given target concentration. In electrochemical sensors thatinclude an auxiliary electrode (e.g., four terminal electrochemicalsensors), auxiliary electrode 218 can be located in close proximity tosensing electrode 202 without being exposed to the reactive gas soauxiliary electrode 218 and sensing electrode 202 can be at the sametemperature. With the auxiliary electrode 218 and the sensing electrode202 at the same temperature (and with auxiliary electrode 218 not beingexposed to the target gas while sensing electrode 202 is exposed to thetarget gas) the signal from auxiliary electrode 218 can be subtractedfrom sensing electrode 202 to compensate for long term drift caused bytemperature effects. Although the above technique can be used for somescenarios (e.g., for conventional uses of these sensors), it has beendetermined that for inhaled NO therapy such techniques may notsufficiently correct for baseline drift.

After extensive research, it was found that when these catalytic typeelectrochemical sensors (e.g., sensors that are suitable for use withlow concentrations of NO or for short periods of time) are usedatypically for inhaled NO therapy, drift may be associated withauxiliary electrode 218 drifting at a differing rate than sensingelectrode 202; temperature changes local to the sensing electrode 202not being detected by auxiliary electrode 218; and/or auxiliaryelectrode 218 heating up at a differing rate than sensing electrode 202.

It was also found that these temperature changes may be caused and/orexacerbated by the target gas (NO) having an exothermic (or endothermic)reaction at one or more of the electrodes (e.g., sensing electrode 202,counter electrode 206, etc.). In some instances, although thesetemperature changes may not be substantial when using these sensors in aconventional manner, these temperature changes may be substantial forthe atypical use of these sensors for inhaled NO therapy, for example,because the concentration of NO used can be substantially higher thanthe concentration that these types of sensors may be exposed toconventionally and/or because the duration of exposure of these sensorswhen used in therapeutic NO delivery can be substantially longer thanthe exposure duration these sensors may have when used conventionallyfor toxic gas emission measurements.

Noting the above, local changes in temperature at sensing electrode 202may not be detected, or may be detected at a different rate, at theauxiliary electrode 218. With this local temperature change at sensingelectrode 202 not also occurring at auxiliary electrode 218, cell “basecurrent” drift may not be corrected, as described above, by simplysubtracting the signal from auxiliary electrode 218 from sensingelectrode 202. Further research also found that if the reactive gas issupplied (e.g., at the same concentration) for a long enough duration oftime (e.g., 24 hours) then the temperature at auxiliary electrode 218may eventually be the same as the temperature at sensing electrode 202,for example, because electrochemical sensor 200 may eventually obtainsteady state, equilibrium, or the like.

Temperature Compensation

In exemplary embodiments, rather than and/or in combination with theabove calibration processes, to address at least some of the abovedescribed surprising phenomena, the local temperature at the sensingelectrode (e.g., at specific times due to a set concentration of NObeing sensed) can be estimated (e.g., mathematically, using heattransfer analysis, etc.). Further, the known signal (e.g., determinedempirically) typically generated by the auxiliary electrode 218 at thatestimated temperature can then be subtracted from the signal generatedby the sensing electrode. Using this technique baseline drift local tothe sensing electrode can be compensated for at specific times. Aftersteady state has been achieved baseline drift related to temperature canbe compensated, as described above, by simply subtracting the signalfrom auxiliary electrode 218 from sensing electrode 202.

By way of example, to determine the local temperature at the sensingelectrode and/or the distribution of heat (or variation in temperature)in electrochemical sensor 200 over time the heat equation can be used.This distribution of heat with respect to time can then be compensatedfor, for example, by subtracting the signal that would be expected tocome from auxiliary electrode 218 if it were at the same temperature assensing electrode 202 from sensing electrode 202.

By way of another example, the local temperature at sensing electrode202 at various times can be determined and/or compensated for usingother methods. For example, a lumped capacitance model can be used. Foranother example, empirical knowledge can be used.

In exemplary embodiments, to address at least some of the abovedescribed phenomena, the electrochemical sensor 200 can be cooled. Thiscooling may need to be substantial enough so that if an exothermicreaction is occurring that heat generated may effectively be dominatedby the cooling temperature. Alternatively, this cooling may need to besubstantial enough so the steady state temperature of electrochemicalsensor 200 may effectively be dominated by the cooling temperature.

In exemplary embodiments, to address at least some of the abovedescribed phenomena, the steady state temperature of electrochemicalsensor 200 and/or the local temperature of the sensing electrode (e.g.,when the steady state is reached) can be determined (e.g.,mathematically, empirically, etc.) and then electrochemical sensor 200can be pre-heated to that temperature or near that temperature, forexample, to reduce the time needed for electrochemical sensor 200 toreach steady state. By way of example, the electrochemical sensor can bepreheated to a known temperature of the sensing electrode for a knownconcentration and then that when that known concentration is added theheat source can be decreased back to the steady state of theelectrochemical sensor (e.g., not the local temperature at the sensingelectrode).

In exemplary embodiments, to address at least some of the abovedescribed phenomena, a secondary sensing electrode (in the same sensoror in a different sensor used in the same NO delivery stream) may beintermittently turned on to provide the appropriate signal output forthe concentration being delivered. The difference between the signaloutput of the sensing electrode and the signal output of this secondarysensing electrode can then be removed (e.g., as it would be related todrift related to temperature) to compensate for zero drift. Thefrequency of the secondary sensing electrode being used can be adjustedwith respect to time. It will be understood that the sensor used (e.g.,primary electrochemical sensor having a primary sensing electrode,secondary electrochemical sensor providing a secondary sensingelectrode, etc.) may be a three terminal (e.g., no auxiliary electrode).

Dual NO Sensors

In exemplary embodiments, the therapeutic gas delivery system caninclude two or more catalytic type electrochemical sensors (e.g., two ormore NO sensors) wherein when one of the sensors is undergoing acalibration (e.g., baseline calibration, etc.) the other sensor isexposed to sample gas from the breathing circuit. Using this technique,when one sensor is offline (e.g., undergoing calibrations, undergoingbaseline calibrations, etc.) the other sensor can be online. Hence, theuser sees no offline period during calibrations and can be provided,without interruption, for example, in the user interface, withconfirmation that the concentration of therapeutic gas the patient isreceiving is the desired set dose. In exemplary embodiments, the sensorscan intermittently monitor (e.g., one sensor can be exposed to samplegas while the other sensor is exposed to zero concentration gas) suchthat neither sensor saturates. In exemplary embodiments, the secondsensor can be used for determination of drift on the same schedule aszeroing.

In contrast to using two sensors to continuously monitor a sample gas,intermittent monitoring reduces the rate at which the sensors age andincreases the amount of time before sensor failure. Continuous exposureof a sensor to low humidity gas can cause the sensor electrolyte to dryout. Using one sensor as a first or primary sensor and a second sensoras a backup sensor results in the sensors being under differentconditions for different lengths of time. In addition, whereascontinuous exposure of both sensors can result in increasing drift ofboth sensors at a comparable rate, which can cause cross-checking to beinaccurate, and may lead to near simultaneous failure of both sensors,intermittent exposure of the backup sensor to the sampler gas in theinspiratory line during calibrations increases the sensors lifespan andallows a cross-check of the primary sensor by a backup sensor withreduced drift. Intermittent use of the backup sensor also avoidssaturation of the sensor with the target gas. Cross-checking allows twosensors to provide two separate calibration values that can be comparedto determine whether the relative amount of drift is greater than athreshold value. If both sensors have similar but excessive drift due toequivalent exposures and aging, the cross-check would give theimpression of less drift than actual.

Sample Gas (Concentration Reduction)

In exemplary embodiments, prior to exposing the catalytic typeelectrochemical sensor (e.g., NO sensor) to sample gas from a breathingcircuit that may contain substantially high concentrations (e.g., >5PPM) of target gas (e.g., NO), the sample gas can be stream blended down(also known as ratio-metric) so the concentration of target gas (e.g.,NO) is reduced by a known amount. The output from the sensor can thenfactor in the known amount the target gas has been diluted to providethe user with confirmation that the therapeutic gas (e.g., NO) is beingdelivered at the desired concentration (e.g., desired set dose). Byreducing the concentration of target gas (e.g., NO) that the sensor(e.g., NO sensor) is exposed to, drift may be reduced and/or eliminatedwhile still enabling monitoring of the set dose being delivered to thepatient.

By way of example, diluent gas flow (e.g., from a source of non-reactivegas, nitrogen gas flow, etc.) can be stream blended proportional tosample gas flow from the breathing circuit to reduce the concentrationof NO in the sample gas. Sample gas flow can be known, for example, asthe sample pump may pull sample gas at a known flow rate, the flow rateof the gas can be controlled, for example, by a valve(s), and/or samplegas flow sensors can measure the flow of sample gas flow. Diluent gasflow (e.g., from a source of non-reactive gas, nitrogen gas flow, etc.)can be known, for example, as it may be provided by and/or pulled by apump; a flow sensor may be used to measure gas flow; and/or the flowrate of the gas can be controlled, for example, by a valve(s).

In exemplary embodiments, the therapeutic gas delivery system canexecute, for example, using machine-executable instructions, a samplegas concentration reduction calculation to blend the sample gas with adiluent gas using diluent gas at known concentration such as nitrogen(e.g., from a nitrogen gas tank); the amount of sample gas flow from thepatient circuit using a sample gas flow sensor and/or the known flow ofa sample pump; and the amount of diluent gas flow reported by a gas flowsensor, the known flow of diluent gas from a diluent gas pump, and/orthe known flow of diluent gas from a flow controller such that the finalNO concentration at the NO sensor would be a fraction concentrationdelivered to the patient. Reducing the average concentration willminimize long term drift. (e.g., valve(s), etc.).

Intermittent Monitoring

In exemplary embodiments, to at least reduce drift of the catalytic typeelectrochemical gas sensor (e.g., NO sensor), the concentration oftherapeutic gas (e.g., set dose of NO) being delivered to the patientmay be monitored intermittently, where the gas sensor is exposed to thetarget gas for a limited period of time rather than continuously. Invarious embodiments, the exposure time may be slightly greater than theresponse time of the sensor. By intermittently monitoring (e.g., ratherthan constantly monitoring) the target gas concentration the amount oftime that the sensor is exposed to the target gas can be reduced, andduring times of non-exposure to the target gas, the sensor can beexposed to ambient air (e.g., conditioned ambient air). This can beaccomplished using catalytic type electrochemical gas sensors (e.g., NOsensors) which have a substantially fast response time (e.g., a fewseconds, less than five seconds, etc.).

By way of example, rather than using a catalytic type electrochemicalsensor (e.g., NO sensor) with a response time of about 15 seconds,catalytic type sensors with a response time of about 5 seconds may beused, where the sensor may be exposed to the target gas (e.g., highconcentration NO) for 5 seconds and exposed to ambient air (e.g.,conditioned ambient air) for 10 seconds and/or for at least some of theremaining 10 seconds. During the period of non-exposure to the targetgas, the output displayed to users by the user interface may be thevalue measured during the period of exposure. Using this techniquesensor drift can be reduced and/or eliminated, while also providingusers with effectively the same desired information (e.g., confirmationthat the desired set dose is being delivered).

Those skilled in the art will readily recognize numerous adaptations andmodifications which can be made to the therapeutic gas delivery systemsand method of delivering a pharmaceutical gas of the present inventionwhich will result in an improved method and system for introducing aknown desired quantity of a pharmaceutical gas into a patient, yet allof which will fall within the scope and spirit of the present inventionas defined in the following claims. Accordingly, the invention is to belimited only by the following claims and their equivalents.

Reference throughout this specification to “one embodiment,” “certainembodiments,” “one or more embodiments,” “exemplary embodiment,”“exemplary embodiments,” and/or “an embodiment” means that a particularfeature, structure, material, or characteristic described in connectionwith the embodiment is included in at least one embodiment of theinvention. Thus, the appearances of the phrases such as “in one or moreembodiments,” “in certain embodiments,” “in one embodiment,” “exemplaryembodiment,” “exemplary embodiments,” and/or “in an embodiment” invarious places throughout this specification are not necessarilyreferring to the same embodiment of the invention. Furthermore, theparticular features, structures, materials, or characteristics can becombined in any suitable manner in one or more embodiments.

It will be understood that any of the steps described can be rearranged,separated, and/or combined without deviated from the scope of theinvention. For ease, steps are, at times, presented sequentially. Thisis merely for ease and is in no way meant to be a limitation. Further,it will be understood that any of the elements and/or embodiments of theinvention described can be rearranged, separated, and/or combinedwithout deviated from the scope of the invention. For ease, variouselements are described, at times, separately. This is merely for easeand is in no way meant to be a limitation. It will be understood that,at times, headings may be used. This is merely for ease and is in no waymeant to be a limitation.

Although the invention herein has been described with reference toparticular embodiments, it is to be understood that these embodimentsare merely illustrative of the principles and applications of thepresent invention. It will be apparent to those skilled in the art thatvarious modifications and variations can be made to the method andapparatus of the present invention without departing from the spirit andscope of the invention. Thus, it is intended that the present inventioninclude modifications and variations that are within the scope of theappended claims and their equivalents.

What is claimed is:
 1. A method for delivering notifications of acalibration status for a sensor associated with a therapeutic gasdelivery device, the method comprising: storing in memory a baselinecalibration value, slope, and calibration schedule; monitoring a patientintake of therapeutic gas with the sensor; delivering, via thetherapeutic gas delivery device, a predetermined dosage of therapeuticgas to the patient; measuring a concentration of therapeutic gas fromthe delivered predetermined dosage; retrieving, from memory, thebaseline calibration value, slope and calibration schedule; performing acalibration according to the calibration schedule, wherein thecalibration includes exposing the sensor to a zero concentration of thetherapeutic gas and adjusting the baseline calibration value accordingto a sensor output value during the calibration; determining, after apredetermined number of calibration attempts, that calibration hasfailed; and notifying a user that calibration has failed.
 2. The methodof claim 1 wherein the therapeutic gas is nitric oxide.
 3. The method ofclaim 1 wherein the user is notified with an alarm.
 4. The method ofclaim 1 wherein the notifying includes displaying a message on a displayscreen.
 5. The method of claim 1 wherein performing the calibrationfurther comprises notifying the user that the calibration is currentlyin effect.
 6. The method of claim 5 wherein the notifying the userfurther comprises displaying a notification that the measuring oftherapeutic gas concentration is off-line.
 7. The method of claim 1wherein the predetermined number of calibration attempts is three. 8.The method of claim 7 wherein the three calibration attempts include afirst initial calibration attempt, and two re-try calibration attempts.9. The method of claim 8 wherein, after the first initial calibrationattempt, the method further comprises re-trying the calibration attemptafter a predetermined period of time has passed.
 10. A method fordelivering notifications of a calibration status for a sensor associatedwith a nitric oxide delivery device, the method comprising: storing inmemory a baseline calibration value, slope, and calibration schedule;monitoring a patient intake of nitric oxide with the sensor; delivering,via the nitric oxide delivery device, a predetermined dosage of nitricoxide to the patient; measuring a concentration of nitric oxide from thedelivered predetermined dosage; retrieving, from memory, the baselinecalibration value, slope and calibration schedule; performing acalibration according to the calibration schedule, wherein thecalibration includes exposing the sensor to a zero concentration of thenitric oxide and adjusting the baseline calibration value according to asensor output value during the calibration; determining, after acalibration attempt, that calibration has failed; notifying a user thatcalibration has failed; and re-attempting the calibration after apredetermined period of time.
 11. The method of claim 10 wherein, uponcompletion of the calibration, the method further comprises determiningan actual concentration of nitric oxide delivered in the predetermineddosage to compensate for sensor drift by adjusting the value of themeasured concentration based on the adjusted baseline value and theslope.
 12. The method of claim 10 further comprising setting a maximumnumber of allowable calibration re-attempts.
 13. The method of claim 12wherein after the maximum number allowable calibration re-attempts, themethod further comprises performing a calibration lockout.
 14. Themethod of claim 13 wherein the calibration lockout further comprisesnotifying the user with an alarm.
 15. The method of claim 10 wherein thecalibration failed because of an improperly functioning valve.
 16. Themethod of claim 10 further comprising determining, after there-attempted calibration, that the calibration failed as a result ofboth calibration attempts producing sensor output values outside anallowable threshold value range.
 17. A method for deliveringnotifications of a calibration status for a sensor associated with anitric oxide delivery device, the method comprising: storing in memory abaseline calibration value, slope, and calibration schedule; monitoringa patient intake of nitric oxide with the sensor; delivering, via thenitric oxide delivery device, a predetermined dosage of nitric oxide tothe patient; measuring a concentration of nitric oxide from thedelivered predetermined dosage; retrieving, from memory, the baselinecalibration value, slope and calibration schedule; performing acalibration according to the calibration schedule, wherein thecalibration includes exposing the sensor to a zero concentration of thenitric oxide and adjusting the baseline calibration value according to asensor output value during the calibration; determining, after acalibration attempt, that calibration has failed; determining that asensor output values is outside an allowable threshold value range;re-attempting the calibration after a predetermined period of time;transmitting a notification to a user that calibration has failed. 18.The method of claim 17 wherein the notification includes displaying thenotification during the performing of the calibration, and furtherincludes displaying the notification for an additional period of timeafter the performing of the calibration is completed.
 19. The method ofclaim 18 wherein the additional period of time corresponds to an amountof time for the sensor to settle.
 20. The method of claim 18 wherein thenitric oxide sensor is exposed to the gas having a zero concentration ofnitric oxide for a predetermined interval before the calibration line isadjusted.